Unraveling the effect of water and ethanol on ibuprofen nanoparticles formation

• Combined experiments and MD simulations of ibuprofen in water and ethanol. • Ibuprofen nanoparticle size strongly depends on the solvent environment. • Dramatic difference in nanoparticle size explained by interaction energies between drug and solvent molecules. • Strategy for nanosizing based on molecular-level insights outlined. In this study, we investigate how water and ethanol affect the formation of ibuprofen sodium salt nanoparticles. Particle sizes were measured with the use of Nanoparticle Tracking Analysis and Transmission Electron Microscopy at concentrations of 30, 50, and 80 mg/mL. In water, nanoparticles had an average size of 93 nm, whereas in ethanol they were significantly smaller, averaging 36 nm. Molecular dynamics simulations revealed that in water, ibuprofen molecules aggregate into clusters of 80–300 molecules. In ethanol, stronger ibuprofen-ethanol interactions lead to the formation of much smaller clusters of 2–3 molecules. Both experimental data and simulations indicate that ethanol is a superior solvent for ibuprofen nanosizing. These findings provide a rational basis for selecting solvents in drug formulation and offer a broader perspective for optimizing drug delivery applications.